PROJECT SUMMARY (ABSTRACT) Lupus nephritis occurs in a majority of patients with systemic lupus erythematosus (SLE, lupus), and is a leading cause of morbidity and mortality. CD4+ and CD8+ T effector cells contribute to the inflammatory response in lupus nephritis in mice and in humans with their renal infiltration correlated to tissue damage and disease severity. Yet, there is limited knowledge of the phenotypic characteristics of the T cells that promote local tissue injury in lupus. The kidney microenvironment becomes hypoxic as a common denominator following a variety of insults, an appropriately physiologic response analogous to that which occurs to ensure lymphocyte survival and effector function during environmental stress, such as at sites of pathogen replication or in tumors. We have shown in preliminary studies that this response in the murine lupus kidney results in tissue adaptive transcriptional and phenotypic changes in renal infiltrating T cells, changes associated with epigenetic modification, with evidence that analogous changes occur in human lupus nephritis. We now propose in this revised application sto explore the hypothesis that environmental stress in the lupus kidney necessarily shapes the phenotypes of renal-infiltrating T cells, with programming for survival and effector function, culminating in tissue injury. We will explore this hypothesis using in vitro and in vivo studies, including genetic and pharmacologic manipulation of tissue adaptive effector pathways in renal T cells, with target confirmation in human lupus nephritis. Our longer term goal, if the current project is successful, is to use this knowledge to re-purpose therapeutic agents currently available for use in humans to treat lupus nephritis.